Polyoxomolybdate Bisphosphonate Heterometallic Complexes: Synthesis, Structure, and Activity on a Breast Cancer Cell Line

Chemistry. 2015 Jul 13;21(29):10537-47. doi: 10.1002/chem.201406565. Epub 2015 Jun 15.

Abstract

Six polyoxometalates containing Mn(II) , Mn(III) , or Fe(III) as the heteroelement were synthesized in water by treating Mo(VI) precursors with biologically active bisphosphonates (alendronate (Ale), zoledronate (Zol), an n-alkyl bisphosphonate (BPC9 ), an aminoalkyl bisphosphonate (BPC8 NH2 )) in the presence of additional metal ions. The Pt complex was synthesized from a polyoxomolybdate bisphosphonate precursor with Mo(VI) ions linked by the 2-pyridyl analogue of alendronate (AlePy). The complexes Mo4 Ale2 Mn, Mo4 Zol2 Mn, Mo4 Ale2 Fe, Mo4 Zol2 Fe, Mo4 (BPC8 NH2 )2 Fe, and Mo4 (BPC9 )2 Fe contain two dinuclear Mo(VI) cores bound to a central heterometallic ion. The oxidation state of manganese was determined by magnetic measurements. Complexes Mo12 (AlePy)4 and Mo12 (AlePy)4 Pt4 were studied by solid-state NMR spectroscopy and the photochromic properties were investigated in the solid state; both methods confirmed the complexation of Pt. Activity against the human breast adenocarcinoma cell line MCF-7 was determined and the most potent compound was Mn(III) -containing Mo4 Zol2 Mn (IC50 ≈1.3 μM). Unlike results obtained with vanadium-containing polyoxometalate bisphosphonates, cell growth inhibition was rescued by the addition of geranylgeraniol, which reverses the effects of bisphosphonates on isoprenoid biosynthesis/protein prenylation. The results indicate an important role for both the heterometallic element and the bisphosphonate ligand in the mechanism of action of the most active compounds.

Keywords: NMR spectroscopy; bisphosphonates; cancer; magnetic properties; polyoxometalates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms
  • Cell Line
  • Crystallography, X-Ray
  • Diphosphonates / chemical synthesis*
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Humans
  • Imidazoles / chemistry*
  • Iron / chemistry
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Manganese / chemistry
  • Molybdenum / chemistry*
  • Molybdenum / pharmacology*
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology*
  • Oxidation-Reduction
  • Zoledronic Acid

Substances

  • Diphosphonates
  • Imidazoles
  • Ligands
  • Organometallic Compounds
  • Manganese
  • Zoledronic Acid
  • Molybdenum
  • Iron